The vasculature of solid tumors is highly defective, resulting in poor blood flow and hypoxia. These defects have profoundly negative consequences for the delivery of chemotherapeutic agents and also for the efficacy of radiation therapy that is oxygen-dependent. The broad long-term objectives of the proposed research are to improve the effectiveness of chemo- and radiation therapies by rectifying key defects in the tumor vasculature. Our recent work has suggested a novel strategy for improving dysfunctional tumor blood vessels with a panel of cytoskeleton-regulating drugs that rectify key defects in neovessels that would otherwise exhibit a pathological phenotype. To apply this new strategy towards improvement of cancer therapies, we propose the following Specific Aims: (1) In mouse models of cancer, employ cytoskeleton-regulating drugs that target Rho GTPase signaling pathways and calpain to rectify important functional defects in the tumor vasculature. Identify combinations of drugs that provide cumulative improvement of tumor vascular perfusion and reduction of hypoxia. (2) Test strategies identified in Aim 1 that maximally increase tumor vascular perfusion and increased tumor oxygenation for improved delivery and efficacy of representative chemotherapeutic agents and improved tumor radiotherapy. Experiments in Aim 1 will define the specific contributions of the various cytoskeleton-regulating drugs, identified in our preliminary studies, to enhance perfusion and oxygenation of important representative tumors and define the optimal dose response and time course for such alterations. Parameters to be measured are improvement of angio-architecture, improved blood flow, increased tumor perfusion, and reduced hypoxia. Depending on findings with each drug individually, we will conduct experiments with combinations of these drugs designed to achieve maximal improvement of tumor perfusion and oxygenation. Experiments in Aim 2 will test the efficacy of the optimal tumor vessel rectifying strategies identified in Aim 1 for improving tumor perfusion and tumor killing using representative chemotherapeutic agents. Experiments in Aim 2 also will test optimal strategies identified in Aim 1 that reduce tumor hypoxia for improved radiation therapy. Validation of this strategy in the proposed preclinical studies offers the prospect of rapid improvement in conventional chemo- and radiation therapies for cancer patients. This is because the several classes of drugs to be used here for stable normalization of pathological tumor blood vessels are actively being pursued as potential therapeutics for other disorders. Thus, implementation of this strategy would not require the extended time and expense typically associated with new drug development. PUBLIC HEALTH RELEVANCE: The goals of this research are to identify and develop new strategies for improving conventional cancer therapies. The blood vessels of tumors are highly abnormal, resulting in poor delivery of chemotherapeutic agents and impaired sensitivity to radiation therapy. Our proposed strategy is to achieve drug-mediated correction of these blood vessel defects in order to increase effectiveness of chemo- and radiation therapies and thereby improve cancer patient survival.